Low‐Dose Combination Therapy: Why Include a Diuretic?

Physicians today face a therapeutic challenge in the treatment of hypertension. We are asked to reduce blood pressure (BP) to below 140/90 mm Hg—or even lower, to below 130/85 mm Hg, in those who also have diabetes or renal disease.1 At present, these levels are attained in fewer than one third of patients.2 What are we doing wrong, and can we fix it? I believe that we can at least improve on our present performance. First, we need to be more aggressive in our approach to treatment. The accumulated evidence from placebo-controlled clinical trials demonstrates that with the drugs in use today, including diuretics, adverse effects are little more frequent or severe than those that occur with placebos. Strokes and heart failure resulting from poorly controlled BP are far more threatening than the possibility of adverse effects. The greatest stumbling block is noncompliance. The Canadian Coalition for Blood Pressure Control3 reported that surveys of noncompliance rates vary widely, but average about 50%, including dropouts. Nonadherence is the major cause of treatment failure. Most patients feel well and are not motivated to faithfully adhere to the daily medication regimen. It is our job, indeed the main focus of our attention, to gain compliance and maintain it over the long haul. This is not easy, but some progress has been made.3–6 Obviously, compliance depends in large part on the confidence the patients have in their physicians. A major factor in gaining this confidence is to achieve goal BP promptly and efficiently. Many physicians begin treatment with a single drug and cautiously titrate it upward, which often requires multiple office visits. How effective is this? Clinical trials indicate that initial treatment with monotherapy, using any of the major classes of drugs, reduces BP to goal levels in about 50% of patients even with titration to optimal dosage.7 The remaining 50% must now be subjected to substitution or addition of a second drug, which, of course, entails a second round of dose adjustment. Then, if the BP is still >140/90 mm Hg, a third drug, or even a fourth, is required. No wonder these patients lose confidence with monotherapy. A recent survey8 showed that 82% of physicians failed to raise doses when indicated. This means that in the real world, considerably fewer than 50% achieve goal BP on initial treatment with monotherapy. Fortunately, there is at least a partial solution to this problem. Instead of using monotherapy as initial treatment, we can substitute low-dose, fixed-dose combination drugs, of which one component is a diuretic. Controlled trials that support this view are described below. The first study is a multiclinic, randomized, double-blind trial in 475 hypertensive patients from the Veterans Administration Cooperative Study Group,9 comparing an angiotensin-converting enzyme (ACE) inhibitor (captopril), first as monotherapy and then in combination with hydrochlorothiazide (HCTZ). BP was reduced after 7 weeks of treatment with captopril alone, by an average 12.2/9.4 mm Hg, and after 7 more weeks on the combined drugs, by a striking 24.4/16.2 mm Hg. By contrast, in another randomized, double-blind trial,10 891 patients received fixed-dose combinations of diltiazem plus enalapril, which were compared with monotherapy with these drugs. Two dose levels of diltiazem were tested (120 and 180 mg), each combined with 5 mg of enalapril. After 12 weeks of treatment, the reduction of diastolic BP with both doses averaged 7.6 and 8.3 mm Hg, respectively, relative to the baseline diastolic BP. These reductions, while significantly greater than achieved with monotherapy, were of far less magnitude than those obtained in the trial described above, which contained a thiazide in the combination. In another double-blind trial,11 218 hypertensive patients were randomly allocated, double-blind, to either amlodipine or enalapril alone, each titrated to optimal dosage, or to a low-dose combination of the β blocker bisoprolol in doses of 2.5, 5, and 10 mg plus 6.25 mg of HCTZ (Ziac®) for 12 weeks. Goal diastolic BP (<90 mm Hg or a reduction by >10 mm Hg) was achieved in 71% of the patients receiving the combination, 69% taking amlodipine and 45% randomized to enalapril. The decreases in systolic/diastolic BP were 13.4/10.7 mm Hg with the combination; 12.8/10.2 mm Hg with amlodipine alone; and 7.3/6.6 mm Hg with enalapril alone. The last trial compared the effectiveness of the major classes of antihypertensive drugs used in two-drug combinations.12 It was preceded by a randomized, double-blind trial that included 1292 men. Atenolol, HCTZ, captopril, diltiazem, clonidine, and prazosin were each given as monotherapy, with the dosage titrated to optimal effect.13,14 The 102 patients who failed to achieve goal diastolic BP of <90 mm Hg after two successive courses of monotherapy were then given a combination of the same drugs that had failed during monotherapy.12 The combinations containing HCTZ as one of the two components reduced systolic BP to <140 mm Hg in 77% of patients, and diastolic BP to <90 mm Hg in 69%, compared to a mean of 46% and 51%, respectively, with the combinations that did not contain a diuretic. Although sample sizes admittedly were small, the differences between the combinations containing HCTZ and the other combinations were significant, which is consistent with the concept that diuretics enhance antihypertensive effectiveness more than other drugs used in two-drug combinations. This is not to say that other combinations may not be more effective than monotherapy with their constituents, but they did not appear to be as effective as the combinations containing small doses of a thiazide diuretic. In the past, diuretics have been accused of adverse cardiovascular and metabolic effects. Moser15,16 and others17 have shown that these claims have been refuted by better controlled data, including data from most large clinical trials and other prospective studies. In fact, the clinical trials indicate that thiazide treatment is associated with a decrease rather than an increase in cardiovascular morbidity and mortality. In addition, the small doses of diuretics used in the combination drugs minimize the risk of any adverse effects. Physicians are taught to always initiate treatment with a single drug. However, there are several advantages to beginning treatment, at least in hypertensive patients, with combination therapy. The recommended goals for BP reduction are more often and more expeditiously achieved with combinations than with monotherapy. Only one pill daily is required, which promotes better compliance. Side effects are infrequent because of the low doses of the constituent drugs, particularly the diuretics. A wide choice of combinations is available, including a low-dose diuretic combined with either a β blocker, ACE inhibitor, angiotensin II receptor antagonist, or calcium channel blocker. Other two-drug combinations are available but may not be as effective as those that include a diuretic.

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